More than 90% of the world population is persistently infected with several herpes viruses. Kaposi's sarcoma-associated herpes virus (KSHV) can establish persistent infection in the oral cavity and can be transmitted orally. KSHV infection manifests in AIDS patients and leads to several lymphoproliferative diseases as well as Kaposi's sarcoma. Although the host cells and the immune system have evolved mechanisms to control herpes viral infections, herpes viruses have also developed strategies to evade and/or antagonize them. Herpes viruses employ multiple viral genes to achieve precise gene expression control and to counteract the host immune system, both of which are essential to establish, maintain, and reactivate from latency. The successful transition between latency and lytic replication is critical for viral persistence in the host. It has not been clearly understood about how the virus regulates its own expression and deregulates cellular transcription to efficiently replicate and evade immune responses. To understand the mechanisms of KSHV persistence, concentrated on at the level of gene expression regulation and immune evasion, four laboratories in California join forces. The following four projects will be primarily addressed: 1) the mechanism of inhibition on type inhibiting interferon production by KSHV ORF36 (project leader: Ren Sun, UCLA);2) the transcriptional regulatory role of ORF36 as the sole viral kinase of KSHV (project leader: Hsing-Jien Kung, UC Davis);3) the mechanism underlying two KSHV-encoded modulators (ORFI0 and ORF45) of innate immune pathways (project leader, Don Ganem, UCSF);4) development of develop a non-human primate model for the KSHV persistent infection of KSHV to determine the immune evasive role of ORFI, ORF36, K-bZIPPRF45 and K5K3 during viral infection in vivo (project leader: Jae Jung, Harvard/USC). Public Relevance: There are extensive interactions among projects, which generate synergy towards one common theme: the virus-host interactions underlying the persistent infection of KSHV. These collaborative activities are facilitated by a Coordination Administration Core. Accomplishing these goals will provide new insight and opportunities to develop novel therapeutic approaches against persistent herpes viral infection and associated diseases. Further, the collaboration stimulated by this program project will not only promote researches outlined in this proposal, but also facilitate joint researches in other aspects of KSHV biology and cultivation of new generation of scientists for multidisciplinary research in the herpes virology field.